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Human neural organoids represent promising models for studying neural function; however, organoids grown in vitro lack certain microenvironments and sensory inputs that are thought to be essential for maturation. The transplantation of patient-derived neural organoids into animal hosts helps overcome some of these limitations and offers an approach for neural organoid maturation and circuit integration. Here, we describe a method for transplanting human stem cell-derived cortical organoids (hCOs) into the somatosensory cortex of newborn rats. The differentiation of human induced pluripotent stem cells into hCOs occurs over 30-60 days, and the transplantation procedure itself requires ~0.5-1 hours per animal. The use of neonatal hosts provides a developmentally appropriate stage for circuit integration and allows the generation and experimental manipulation of a unit of human neural tissue within the cortex of a living animal host. After transplantation, animals can be maintained for hundreds of days, and transplanted hCO growth can be monitored by using brain magnetic resonance imaging. We describe the assessment of human neural circuit function in vivo by monitoring genetically encoded calcium responses and extracellular activity. To demonstrate human neuron-host functional integration, we also describe a procedure for engaging host neural circuits and for modulating animal behavior by using an optogenetic behavioral training paradigm. The transplanted human neurons can then undergo ex vivo characterization across modalities including dendritic morphology reconstruction, single-nucleus transcriptomics, optogenetic manipulation and electrophysiology. This approach may enable the discovery of cellular phenotypes from patient-derived cells and uncover mechanisms that contribute to human brain evolution from previously inaccessible developmental stages., (© 2024. Springer Nature Limited.)

Animals must continually evaluate stimuli in their environment to decide which opportunities to pursue, and in many cases these decisions can be understood in fundamentally economic terms. Although several brain regions have been individually implicated in these processes, the brain-wide mechanisms relating these regions in decision-making are unclear. Using an economic decision-making task adapted for rats, we find that neural activity in both of two connected brain regions, the ventrolateral orbitofrontal cortex (OFC) and the dorsomedial striatum (DMS), was required for economic decision-making. Relevant neural activity in both brain regions was strikingly similar, dominated by the spatial features of the decision-making process. However, the neural encoding of choice direction in OFC preceded that of DMS, and this temporal relationship was strongly correlated with choice accuracy. Furthermore, activity specifically in the OFC projection to the DMS was required for appropriate economic decision-making. These results demonstrate that choice information in the OFC is relayed to the DMS to lead accurate economic decision-making., (© 2023. The Author(s).)

Self-organizing neural organoids represent a promising in vitro platform with which to model human development and disease 1-5 . However, organoids lack the connectivity that exists in vivo, which limits maturation and makes integration with other circuits that control behaviour impossible. Here we show that human stem cell-derived cortical organoids transplanted into the somatosensory cortex of newborn athymic rats develop mature cell types that integrate into sensory and motivation-related circuits. MRI reveals post-transplantation organoid growth across multiple stem cell lines and animals, whereas single-nucleus profiling shows progression of corticogenesis and the emergence of activity-dependent transcriptional programs. Indeed, transplanted cortical neurons display more complex morphological, synaptic and intrinsic membrane properties than their in vitro counterparts, which enables the discovery of defects in neurons derived from individuals with Timothy syndrome. Anatomical and functional tracings show that transplanted organoids receive thalamocortical and corticocortical inputs, and in vivo recordings of neural activity demonstrate that these inputs can produce sensory responses in human cells. Finally, cortical organoids extend axons throughout the rat brain and their optogenetic activation can drive reward-seeking behaviour. Thus, transplanted human cortical neurons mature and engage host circuits that control behaviour. We anticipate that this approach will be useful for detecting circuit-level phenotypes in patient-derived cells that cannot otherwise be uncovered., (© 2022. The Author(s).)

Steroid-induced osteonecrosis of the femoral head (SONFH) is a condition documented in humans and animals exposed to chronic steroid administration. The rabbit has become a preferred animal model for investigating the pathogenesis and treatment of SONFH due to its shared femoral vascular anatomy with human patients, relative size of the femoral head, and general fecundity. However, morbidity and mortality are frequent during the steroid induction period, prior to surgical manipulation. These problems are poorly reported and inadequately described in the literature. In this study, we report the clinical, gross, and histopathologic findings of New Zealand white (NZW) rabbits undergoing the steroid induction phase of the SONFH model. Severe weight loss (>30%), lipemia, hypercholesterolemia, hyperglycemia, and elevations in ALT and AST were consistent findings across all rabbits, although these changes did not differentiate asymptomatic rabbits from those that became clinically symptomatic or died. Euthanized and spontaneously deceased rabbits exhibited hepatomegaly, hepatic lipidosis/glycogenosis, and hepatocellular necrosis, in addition to a lipid-rich and proteinaceous thoracic effusion. A subset of rabbits developed opportunistic pulmonary infections with Bordetella bronchiseptica and Escherichia coli and small intestine infections with Lawsonia intracellularis superimposed on hepatic and thoracic disease. Together, these findings allowed us to establish a clinical decision-making flowchart that reduced morbidities and mortalities in a subsequent cohort of SONFH rabbits. Recognition of these model-associated morbidities is critical for providing optimal clinical care during the disease induction phase of SONFH.

Achieving temporally precise, noninvasive control over specific neural cell types in the deep brain would advance the study of nervous system function. Here we use the potent channelrhodopsin ChRmine to achieve transcranial photoactivation of defined neural circuits, including midbrain and brainstem structures, at unprecedented depths of up to 7 mm with millisecond precision. Using systemic viral delivery of ChRmine, we demonstrate behavioral modulation without surgery, enabling implant-free deep brain optogenetics.

Advanced imaging methods now allow cell-type-specific recording of neural activity across the mammalian brain, potentially enabling the exploration of how brain-wide dynamical patterns give rise to complex behavioural states 1-12 . Dissociation is an altered behavioural state in which the integrity of experience is disrupted, resulting in reproducible cognitive phenomena including the dissociation of stimulus detection from stimulus-related affective responses. Dissociation can occur as a result of trauma, epilepsy or dissociative drug use 13,14 , but despite its substantial basic and clinical importance, the underlying neurophysiology of this state is unknown. Here we establish such a dissociation-like state in mice, induced by precisely-dosed administration of ketamine or phencyclidine. Large-scale imaging of neural activity revealed that these dissociative agents elicited a 1-3-Hz rhythm in layer 5 neurons of the retrosplenial cortex. Electrophysiological recording with four simultaneously deployed high-density probes revealed rhythmic coupling of the retrosplenial cortex with anatomically connected components of thalamus circuitry, but uncoupling from most other brain regions was observed-including a notable inverse correlation with frontally projecting thalamic nuclei. In testing for causal significance, we found that rhythmic optogenetic activation of retrosplenial cortex layer 5 neurons recapitulated dissociation-like behavioural effects. Local retrosplenial hyperpolarization-activated cyclic-nucleotide-gated potassium channel 1 (HCN1) pacemakers were required for systemic ketamine to induce this rhythm and to elicit dissociation-like behavioural effects. In a patient with focal epilepsy, simultaneous intracranial stereoencephalography recordings from across the brain revealed a similarly localized rhythm in the homologous deep posteromedial cortex that was temporally correlated with pre-seizure self-reported dissociation, and local brief electrical stimulation of this region elicited dissociative experiences. These results identify the molecular, cellular and physiological properties of a conserved deep posteromedial cortical rhythm that underlies states of dissociation.

The central amygdala (CeA) orchestrates adaptive responses to emotional events. While CeA substrates for defensive behaviors have been studied extensively, CeA circuits for appetitive behaviors and their relationship to threat-responsive circuits remain poorly defined. Here, we demonstrate that the CeA sends robust inhibitory projections to the lateral substantia nigra (SNL) that contribute to appetitive and aversive learning in mice. CeA→SNL neural responses to appetitive and aversive stimuli were modulated by expectation and magnitude consistent with a population-level salience signal, which was required for Pavlovian conditioned reward-seeking and defensive behaviors. CeA→SNL terminal activation elicited reinforcement when linked to voluntary actions but failed to support Pavlovian associations that rely on incentive value signals. Consistent with a disinhibitory mechanism, CeA inputs preferentially target SNL GABA neurons, and CeA→SNL and SNL dopamine neurons respond similarly to salient stimuli. Collectively, our results suggest that amygdala-nigra interactions represent a previously unappreciated mechanism for influencing emotional behaviors., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Thirty-day mortality after chemotherapy has been suggested as a marker of quality in oncology care. Retrospective audits worldwide have put this figure at between 8.1% and 43%, with previous retrospective Australian audits putting this figure at between 3.4% and 18%. To date, there has not been a prospective cohort study of patients receiving palliative intent chemotherapy at an Australian chemotherapy day unit., Aim: The aim of the study is to benchmark 30-day mortality for patients receiving palliative intent chemotherapy and identify associated factors at an Australian tertiary cancer centre., Methods and Results: A prospective cohort study of all patients with a diagnosis of malignancy referred for palliative intent intravenous chemotherapy to the Sunshine Hospital Chemotherapy Day Unit over a 12-month period. The primary outcome was death within 30 days of receiving palliative intent chemotherapy. Other outcome measures included place of death and whether the patient received an outpatient palliative care referral. A total of 314 patients were enrolled in the study, and 98 patients died within the audit period. Of these, 21 (6.6%) died within 30 days of commencing palliative intent chemotherapy, and 60 (18.8%) died more than 30 days after receiving chemotherapy. Of the 34 patients that were referred, but did not start chemotherapy, 18 (52%) died. Multivariable logistic regression found that patients who received an outpatient palliative care referral and received chemotherapy were more likely to die within 30 days, although these did not reach statistical significance., Conclusion(s): This prospective cohort study demonstrated that 6.6% of patients died within 30 days of the administration of palliative intent chemotherapy; however, none of the prespecified factors were found to be statistically significantly associated with 30-day mortality., (© 2018 Wiley Periodicals, Inc.)

A wireless electrical stimulation implant for peripheral nerves, achieving >10× improvement over state of the art in the depth/volume figure of merit, is presented. The fully integrated implant measures just 2 mm × 3 mm × 6.5 mm (39 mm 3 , 78 mg), and operates at a large depth of 10.5 cm in a tissue phantom. The implant is powered using ultrasound and includes a miniaturized piezoelectric receiver (piezo), an IC designed in 180 nm HV BCD process, an off-chip energy storage capacitor, and platinum stimulation electrodes. The package also includes an optional blue light-emitting diode for potential applications in optogenetic stimulation in the future. A system-level design strategy for complete operation of the implant during the charging transient of the storage capacitor, as well as a unique downlink command/data transfer protocol, is presented. The implant enables externally programmable current-controlled stimulation of peripheral nerves, with a wide range of stimulation parameters, both for electrical (22 to 5000 μA amplitude, ∼14 to 470 μs pulse-width, 0 to 60 Hz repetition rate) and optical (up to 23 mW/mm 2 optical intensity) stimulation. Additionally, the implant achieves 15 V compliance voltage for chronic applications. Full integration of the implant components, end-to-end in vitro system characterizations, and results for the electrical stimulation of a sciatic nerve, demonstrate the feasibility and efficacy of the proposed stimulator for peripheral nerves.

All organisms must solve the same fundamental problem: they must acquire rewards and avoid danger in order to survive. A key challenge for the nervous system is therefore to connect motivationally salient sensory stimuli to neural circuits that engage appropriate valence-specific behavioral responses. Anatomical, behavioral, and electrophysiological data have long suggested that the amygdala plays a central role in this process. Here we review experimental efforts leveraging recent technological advances to provide previously unattainable insights into the functional, anatomical, and genetic identity of neural populations within the amygdala that connect sensory stimuli to valence-specific behavioral responses., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Given that low- and middle-income countries (LMICs) in Asia still have high child mortality rates, improved monitoring using children's environmental health indicators (CEHI) may help reduce preventable deaths by creating healthy environments., Objectives: Thus, the aim of this study is to build a set of targeted CEHI that can be applied in LMICs in Asia through the CEHI initiative using a common conceptual framework., Methods: A systematic review was conducted to identify the most frequently used framework for developing CEHI. Due to the limited number of eligible records, a hand search of the reference lists and an extended search of Google Scholar were also performed. Based on our findings, we designed a set of targeted CEHI to address the children's environmental health situation in LMICs in Asia. The Delphi method was then adopted to assess the relevance, appropriateness, and feasibility of the targeted CEHI., Findings: The systematic review indicated that the Driving-Pressure-State-Exposure-Effect-Action framework and the Multiple-Exposures-Multiple-Effects model were the most common conceptual frameworks for developing CEHI. The Multiple-Exposures-Multiple-Effects model was adopted, given that its population of interest is children and its emphasis on the many-to-many relationship. Our review also showed that most of the previous studies covered upper-middle- or high-income countries. The Delphi results validated the targeted CEHI. The targeted CEHI were further specified by age group, gender, and place of residence (urban/rural) to enhance measurability., Conclusions: Improved monitoring systems of children's environmental health using the targeted CEHI may mitigate the data gap and enhance the quality of data in LMICs in Asia. Furthermore, critical information on the complex interaction between the environment and children's health using the CEHI will help establish a regional environmental children's health action plan, named "The Children's Environment and Health Action Plan for Asia.", (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Adverse environmental exposures in early life increase the risk of chronic disease but do not attract the attention nor receive the public health priority warranted. A safe and healthy environment is essential for children's health and development, yet absent in many countries. A framework that aids in understanding the link between environmental exposures and adverse health outcomes are environmental health indicators-numerical estimates of hazards and outcomes that can be applied at a population level. The World Health Organization (WHO) has developed a set of children's environmental health indicators (CEHI) for physical injuries, insect-borne disease, diarrheal diseases, perinatal diseases, and respiratory diseases; however, uptake of steps necessary to apply these indicators across the WHO regions has been incomplete. A first indication of such uptake is the management of data required to measure CEHI., Objectives: The present study was undertaken to determine whether Australia has accurate up-to-date, publicly available, and readily accessible data on each CEHI for indigenous and nonindigenous Australian children., Findings: Data were not readily accessible for many of the exposure indicators, and much of the available data were not child specific or were only available for Australia's indigenous population. Readily accessible data were available for all but one of the outcome indicators and generally for both indigenous and nonindigenous children. Although Australia regularly collects data on key national indicators of child health, development, and well-being in several domains mostly thought to be of more relevance to Australians and Australian policy makers, these differ substantially from the WHO CEHI., Conclusions: The present study suggests that the majority of these WHO exposure and outcome indicators are relevant and important for monitoring Australian children's environmental health and establishing public health interventions at a local and national level and collection of appropriate data would inform public health policy in Australia., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Understanding brain function requires knowing both how neural activity encodes information and how this activity generates appropriate responses. Electrophysiological, imaging and immediate early gene immunostaining studies have been instrumental in identifying and characterizing neurons that respond to different sensory stimuli, events and motor actions. Here we highlight approaches that have manipulated the activity of physiologically classified neurons to determine their role in the generation of behavioural responses. Previous experiments have often exploited the functional architecture observed in many cortical areas, where clusters of neurons share response properties. However, many brain structures do not exhibit such functional architecture. Instead, neurons with different response properties are anatomically intermingled. Emerging genetic approaches have enabled the identification and manipulation of neurons that respond to specific stimuli despite the lack of discernable anatomical organization. These approaches have advanced understanding of the circuits mediating sensory perception, learning and memory, and the generation of behavioural responses by providing causal evidence linking neural response properties to appropriate behavioural output. However, significant challenges remain for understanding cognitive processes that are probably mediated by neurons with more complex physiological response properties. Currently available strategies may prove inadequate for determining how activity in these neurons is causally related to cognitive behaviour., (© 2015 The Author(s) Published by the Royal Society. All rights reserved.)

Stimuli that possess inherently rewarding or aversive qualities elicit emotional responses and also induce learning by imparting valence upon neutral sensory cues. Evidence has accumulated implicating the amygdala as a critical structure in mediating these processes. We have developed a genetic strategy to identify the representations of rewarding and aversive unconditioned stimuli (USs) in the basolateral amygdala (BLA) and have examined their role in innate and learned responses. Activation of an ensemble of US-responsive cells in the BLA elicits innate physiological and behavioral responses of different valence. Activation of this US ensemble can also reinforce appetitive and aversive learning when paired with differing neutral stimuli. Moreover, we establish that the activation of US-responsive cells in the BLA is necessary for the expression of a conditioned response. Neural representations of conditioned and unconditioned stimuli therefore ultimately connect to US-responsive cells in the BLA to elicit both innate and learned responses., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Adolescence and young adulthood offer opportunities for health gains both through prevention and early clinical intervention. Yet development of health information systems to support this work has been weak and so far lagged behind those for early childhood and adulthood. With falls in the number of deaths in earlier childhood in many countries and a shifting emphasis to non-communicable disease risks, injuries, and mental health, there are good reasons to assess the present sources of health information for young people. We derive indicators from the conceptual framework for the Series on adolescent health and assess the available data to describe them. We selected indicators for their public health importance and their coverage of major health outcomes in young people, health risk behaviours and states, risk and protective factors, social role transitions relevant to health, and health service inputs. We then specify definitions that maximise international comparability. Even with this optimisation of data usage, only seven of the 25 indicators, covered at least 50% of the world's adolescents. The worst adolescent health profiles are in sub-Saharan Africa, with persisting high mortality from maternal and infectious causes. Risks for non-communicable diseases are spreading rapidly, with the highest rates of tobacco use and overweight, and lowest rates of physical activity, predominantly in adolescents living in low-income and middle-income countries. Even for present global health agendas, such as HIV infection and maternal mortality, data sources are incomplete for adolescents. We propose a series of steps that include better coordination and use of data collected across countries, greater harmonisation of school-based surveys, further development of strategies for socially marginalised youth, targeted research into the validity and use of these health indicators, advocating for adolescent-health information within new global health initiatives, and a recommendation that every country produce a regular report on the health of its adolescents., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Rationale: Reconsolidation is the process by which memories require restabilisation following destabilisation at retrieval. Since even old, well-established memories become susceptible to disruption following reactivation, treatments based upon disrupting reconsolidation could provide a novel form of therapy for neuropsychiatric disorders based upon maladaptive memories, such as drug addiction. Pavlovian cues are potent precipitators of relapse to drug-seeking behaviour and influence instrumental drug seeking through at least three psychologically and neurobiologically distinct processes: conditioned reinforcement, conditioned approach (autoshaping) and conditioned motivation (pavlovian-instrumental transfer or PIT). We have previously demonstrated that the reconsolidation of memories underlying the conditioned reinforcing properties of drug cues depends upon NMDA receptor (NMDAR)- and β-adrenergic receptor (βAR)-mediated signalling. However, it is unknown whether the drug cue memory representations underlying conditioned approach and PIT depend upon the same mechanisms., Objectives: Using orally self-administered ethanol as a reinforcer in two separate experiments, we investigated whether the reconsolidation of the memories underlying conditioned approach and PIT requires βAR- and NMDAR-dependent neurotransmission., Results: For ethanol self-administering but non-dependent rats, the memories underlying conditioned approach and PIT for a pavlovian drug cue were disrupted by the administration of the NMDAR antagonist MK-801, but not the administration of the βAR antagonist propranolol, when given in conjunction with memory reactivation., Conclusions: As for natural reinforcers, NMDARs are required for the reconsolidation of all aspects of pavlovian drug memories, but βARs are only required for the memory representation underlying conditioned reinforcement. These results indicate the potential utility of treatments based upon disrupting cue-drug memory reconsolidation in preventing relapse.

Chemical elements such as selenium, fluoride, iron, calcium and magnesium are essential to the human being, although some are toxic when absorbed in high doses. In this paper, the risks associated with insufficient and excessive intake of selenium in the diet are reviewed, focusing on drinking water. Two different approaches are used to derive recommended nutrient intakes (RNI) for adequate nutritional status and guideline values to prevent excessive exposure. The former is based on the daily intake which meets the nutrient requirements of 97.5% of the population. The latter is a value derivation based on an assumed daily per capita consumption at the individual level, a conservative approach used where there is any uncertainty and is related to a negligible risk to health at population level across life stages. There is an increasing need to develop a conceptual framework bringing together aspects of toxicity and essentiality especially for elements apparently exhibiting narrow or overlapping ranges between essentiality and toxicity and to provide guidance on the nature and severity of risks in order to better protect human. While there are a number of frameworks available, these generally only consider food. There is a need to include water, which can be a significant source in some circumstances.

A WHO methodology is used for the first time to estimate the burden of disease directly associated with incomplete water and sanitation provision in refugee camps in sub-Saharan African countries. In refugee camps of seven countries, containing just fewer than 1 million people in 2005, there were 132,000 cases of diarrhoea and over 280,000 reported cases of malaria attributable to incomplete water and sanitation provision. In the period from 2005 to 2007 1,400 deaths were estimated to be directly attributable to incomplete water and sanitation alone in refugee camps in Ethiopia, Kenya and Tanzania. A comparison with national morbidity estimates from WHO shows that although diarrhoea estimates in the camps are often higher, mortality estimates are generally much lower, which may reflect on more ready access to medical aid within refugee camps. Despite the many limitations, these estimates highlight the burden of disease connected to incomplete water and sanitation provision in refugee settings and can assist resource managers to identify camps requiring specific interventions. Additionally the results reinforce the importance of increasing dialogue between the water, sanitation and health sectors and underline the fact that efforts to reduce refugee morbidity would be greatly enhanced by strengthening water and sanitation provision.

A working group coordinated by the World Health Organization developed a set of indicators to protect children's health from environmental risks and to support current and future European policy needs. On the basis of identified policy needs, the group developed a core set of 29 indicators for implementation plus an extended set of eight additional indicators for future development, focusing on exposure, health effects, and action. As far as possible, the indicators were designed to use existing information and are flexible enough to be developed further to meet the needs of policy makers and changing health priorities. These indicators cover most of the priority topic areas specified in the Children's Environment and Health Action Plan for Europe (CEHAPE) as adopted in the Fourth Ministerial Conference on Health and Environment in 2004, and will be used to monitor the implementation of CEHAPE. This effort can be viewed as an integral part of the Global Initiative on Children's Environmental Health Indicators, launched at the World Summit on Sustainable Development in 2002.

This paper outlines briefly how the living environment can affect health. It explains the links between social and environmental determinants of health in urban settings. Interventions to improve health equity through the environment include actions and policies that deal with proximal risk factors in deprived urban areas, such as safe drinking water supply, reduced air pollution from household cooking and heating as well as from vehicles and industry, reduced traffic injury hazards and noise, improved working environment, and reduced heat stress because of global climate change. The urban environment involves health hazards with an inequitable distribution of exposures and vulnerabilities, but it also involves opportunities for implementing interventions for health equity. The high population density in many poor urban areas means that interventions at a small scale level can assist many people, and existing infrastructure can sometimes be upgraded to meet health demands. Interventions at higher policy levels that will create more sustainable and equitable living conditions and environments include improved city planning and policies that take health aspects into account in every sector. Health equity also implies policies and actions that improve the global living environment, for instance, limiting greenhouse gas emissions. In a global equity perspective, improving the living environment and health of the poor in developing country cities requires actions to be taken in the most affluent urban areas of the world. This includes making financial and technical resources available from high-income countries to be applied in low-income countries for urgent interventions for health equity. This is an abbreviated version of a paper on "Improving the living environment" prepared for the World Health Organization Commission on Social Determinants of Health, Knowledge Network on Urban Settings.